We have carried out a series of studies in patients with primary biliary cirrhosis (PBC), an idiopathic disease characterized by inflammation and necrosis of intrahepatic bile ducts, often associated with systemic autoimmune features. To study the possibility that autoimmune features of PBC may be due to B cell abnormalities, we studied B cells for evidence of activation. PBC patients had an increased proportion of a normally very small population of circulating immunoglobulin secreting cells in peripheral blood. However, the majority of B cells were found to lack increased expression of transferrin receptor, which we have shown to be associated with B cell activation. These findings indicate that only a small population of activated B cells may contribute to the autoimmune proces.. In other studies we found that patients with PBC have deficient natural killer cell activity in peripheral blood, which was shown to be due to deficient lytic activity of NK cells. The deficiency of NK activity in PBC may reflect a more generalized abanormality related to other previously described lymphocyte abnormalities in this disease. Finally, we studied a family in which multiple patients had PBC, liver disease, and autoimmunity, and found one family member with selective IgA deficiency. This finding indicates that the IgA immune system, of which the hepatobiliary system is a part, is not necessary for the pathogenesis of PBC.